Última actualización:
September 09, 2020
Años publicados: 2002, 2003, 2014, 2017, 2020
NORD gratefully acknowledges Jacqueline T. Hecht, PhD, Professor and Division Head, Pediatric Research Center and Vice Chair for Research, Leah L. Lewis Distinguished Chair, Department of Pediatrics, UTHealth McGovern Medical School, for assistance in the preparation of this report.
Summary
Pseudoachondroplasia (PSACH) is a short-limbed dwarfing condition characterized by disproportionate short stature, normal facial features and head size, and early onset osteoarthritis; intelligence is normal. There is marked laxity in the fingers, wrists, elbows and knees. Joint pain is common at all ages; osteoarthritis occurs in early adulthood and affects all the joints. Scoliosis or abnormal curvature of the spine and cervical spine instability are complications. Pseudoachondroplasia is caused by a change (mutation) in the cartilage oligomeric matrix protein (COMP) gene and is transmitted in an autosomal dominant pattern. Thirty percent of cases are familial with an affected parent transmitting the condition, while 70% occur as a random, new (de novo) mutation in COMP with no previous family history.
Introduction
Pseudoachondroplasia was first described in 1959 by Drs. Maroteaux and Lamy and was originally considered to be a type of spondyloepiphyseal dysplasia. It is now classified as a COMPopathy in the category of multiple epiphyseal dysplasia. While four different forms were previously reported based on severity and inheritance pattern in case reports, pseudoachondroplasia is now known to be a single, distinct disorder caused by mutations in the COMP gene.
Pseudoachondroplasia shows variable expression with the severity varying within and between families. Infants with pseudoachondroplasia have normal birth parameters and cannot be distinguished from unaffected newborns. Generally, the first sign is diminished linear growth starting between 9 to 12 months first affecting length and eventually height, falling approximately two years behind the standard growth curve. Disproportionate short stature becomes more apparent with age. Affected children usually begin to walk between 12-18 months but gait is abnormal and described as ‘waddling’ reflecting underlying skeletal abnormalities involving the hips. The face has been described as angular. Disproportionate shortening of the arms and legs becomes apparent between 3-5 years of age. The hands and toes are very short, have redundant skin folds and marked joint laxity. Interestingly in contrast, the elbow may have limited extension. Joint laxity at the knees contributes to the lower extremity deformities that range from bowing (genu varum), knock knee (genu valgum) deformities or bowing in one leg and a knock knee deformity in the other called a windswept deformity. Surgical correction is generally required but should be delayed to get maximum sustainable correction.
Spinal abnormalities are common and include: 1) scoliosis or S-shaped spinal curve 2) exaggerated lumbar lordosis, which is an abnormal inward curvature of the lower portion of the spine and 3) kyphosis, which is abnormal front-to-back (or outward) curvature of the spine so that the spine is abnormally rounded at the top. Underdevelopment (hypoplasia) of the small, tooth-like projection (odontoid) at the top of the spine can occur. Odontoid hypoplasia causes instability in the neck region (cervical instability), which increases the risk of spinal injury (cervical myelopathy). This complication requires surgical fusion of the upper spine.
Pain, a common and universal complaint, starts in early childhood and is exacerbated by exercise. Activities that stress the joints should be avoided including all contact sports and the trampoline. Early joint pain may reflect an inflammatory process related to the underlying chondrocyte pathology. Osteoarthritis in early adulthood is a universal finding usually developing into chronic joint pain (arthralgia) specifically affecting the hips, ankles, shoulder, elbows and wrists. Degenerative joint disease is progressive and ultimately may require surgery starting with hip replacement followed by other joint replacements. Symptomatic treatment with anti-inflammatory medications is used for pain management with varying degrees of success.
Final adult height on average is 3’8” (116 cm) for women and 3’9” for men (120 cm) but this can vary as some individuals may attain a height of 4’10”. Intelligence and life expectancy are unaffected and most individuals raise families and lead productive, active and full lives.
Mutations in the COMP gene cause pseudoachondroplasia. Genes provide instructions for creating proteins that play critical roles in many functions of the body. When a gene mutation occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. COMP mutations specifically affect chondrocytes in the growth centers, which are the cells that specify for linear growth. The articular cartilage at the ends of all the long bones also contains chondrocytes and is easily eroded causing osteoarthritis and painful joints.
Approximately 70% of cases occur as a new (sporadic or de novo) mutation, which means that in the majority of cases, the gene mutation occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. In this case, the disorder is usually not inherited from an affected parent. However, once the mutation has occurred, it is transmitted in a dominant pattern from the affected individual to their child. Dominant genetic disorders occur when only a single copy of an abnormal gene is present. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the child.
Recurrence was reported in a few families in what appeared to be autosomal recessive inheritance. Mutational analysis revealed that these cases were the result of parental germline mosaicism for a COMP mutation. As a result, one or more of the parent’s children may inherit the germline COMP mutation, leading to pseudoachondroplasia, while the parent does not have this disorder because the mutation is not present in sufficient number of body cells. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy for familial cases with a known mutation is commercially available and should be discussed with a genetic specialist.
The exact birth prevalence of pseudoachondroplasia is unknown, but estimated to be 1 in 50,000-100,000. Males and females are equally affected.
The diagnosis of pseudoachondroplasia is based upon identification of characteristic clinical and radiographic findings, detailed patient history and mutational testing. The diagnosis is rarely made at birth because short stature is not present. The distinctive features develop over time, and this sets it apart from other short stature conditions.
Clinical Testing and Workup
A complete set of x-rays (radiographs) establishes the diagnosis by revealing abnormal growth centers (epiphyses) and other characteristic skeletal findings. The diagnosis is made clinically and by radiographs. More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used later to assess skeletal health, particular in advance of surgery to correct skeletal malformations.
Commercial sequencing of a patient’s COMP gene is available, confirming the diagnosis and identifying he exact mutation. Prenatal diagnosis for pregnancies at increased risk for pseudoachondroplasia is accomplished by chorionic villus sampling or amniocentesis, regardless of whether the COMP mutation has been identified in an affected family member.
Genetic counseling is recommended to help families understand the genetics and natural history of pseudoachondroplasia and to provide psychosocial support.
Treatment
Treatments are directed toward the specific symptoms as they become apparent and usually require the coordinated efforts of a team of specialists. The team includes geneticists, pediatricians, specialists in treating skeletal disorders (orthopedic surgeons), neurologists, physical and occupational therapists and other healthcare professionals who will systematically and comprehensively plan needed treatments.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of painful symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Pain medications may be beneficial in treating pain associated with joint disease. Physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial.
Spinal abnormalities, in some children, may require surgical intervention. Abnormal curvature of the spine, e.g. scoliosis, usually does not require surgery, but in severe cases, surgery has been effective. More serious spinal problems such as cervical instability may require spinal fusion. Surgical realignment of the lower extremities, called osteotomy, is often required before adulthood. Total hip replacement surgery (total hip arthroplasty) occurs in more than 50% of individuals.
There is currently one clinical trial (NCT03866200 clinicaltrials.gov) testing the efficacy of resveratrol, an antioxidant, in pseudoachondroplasia adults. Resveratrol has been shown, in a mouse model of pseudoachondroplasia, to decrease inflammation, restore some long bone growth and, likely decrease pain.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., short stature, skeletal abnormalities, etc.)
TEXTBOOKS
Jones KL, Jones MC, del Campo Casanelles. Eds. Pseudoachondroplasia. In: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:464-465.
JOURNAL ARTICLES
Posey KL, Coustry F, Hecht JT. Cartilage oligomeric matrix protein: COMPopathies and beyond. Matrix Biol. 2018 Oct;71-72:161-173. doi: 10.1016/j.matbio.2018.02.023. Epub 2018 Mar 9.PMID: 29530484 https://pubmed.ncbi.nlm.nih.gov/29530484/
Posey KL, Hecht JT. Novel therapeutic interventions for pseudoachondroplasia. Bone. 2017 Sep;102:60-68. doi: 10.1016/j.bone.2017.03.045. Epub 2017 Mar 21.PMID: 28336490 https://www.sciencedirect.com/science/article/abs/pii/S8756328217301151
Posey KL, Alcorn JL, Hecht JT. Pseudoachondroplasia/COMP – translating from the bench to bedside. Matrix Biol. 2014;37C:167-173. https://www.ncbi.nlm.nih.gov/pubmed/24892720
Jackson GC, Mittaz-Crettol L, Taylor JA, et al.
Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat. 2012;33:144-157. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272220/
Li QW, Song HR, Mahajan RH, Suh SW, Lee SH. Deformity correction with external fixator in pseudoachondroplasia. Clin Orthop Relat Res. 2007;454:174-179. https://www.ncbi.nlm.nih.gov/pubmed/16957646
Kennedy J, Jackson G, Ramsden S, et al. COMP mutation screening as an aid for the clinical diagnosis and counseling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. Eur J Hum Genet. 2005;13:547-555. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673054/
INTERNET
Briggs MD, Wright MJ. Pseudoachondroplasia. 2004 Aug 20 [Updated 2018 Aug 16]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1487/ Accessed Accessed August 12, 2020.
Le Merrer M. Pseudoachondroplasia. Orphanet Encyclopedia. November 2008. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=2676&Disease_Disease_Search_diseaseGroup=Pseudoachondroplasia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Pseudoachondroplasia&title=Pseudoachondroplasia&search=Disease_Search_Simple%20 Accessed August 12, 2020.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:177170; Last Update: 08/09/2018. Available at:https://omim.org/entry/177170 Accessed August 12, 2020.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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